Very low density lipoprotein (VLDL) is a component of all human lipid profiles and increases in plasma concentration after the consumption of fatty meals. VLDL is converted to low density lipoprotein (LDL) by the enzyme lipoprotein lipase (LPL), a homodimeric enzyme that attaches the amino-glycan surface of the endothelium. The action of LPL is the liberation of free fatty acids (FFA) from the triglycerides present specifically in the VLDL particle. In the LPL mediated lipid hydrolysis, FFA are generated and subsequently transported into the adjacent cells. During this process, the VLDL reduces in physical size (due to decreased lipid content) and converted to LDL, at which time the particle is released back into the blood stream and subsequently proceeds to the liver. This transformation of the lipid particle from VLDL to LDL by LPL also results in altered apolipoprotein content of the particles. One apolipoprotein, apolipoprotein CM (ApoCIII), is a heterogeneous protein that constitutes on average 53% of the apoliprotein content of VLDL particles. The resultant LDL particle is essentially devoid of ApoCIII, as it is released free into the blood stream during the LPL digestion process.
ApoCIII is an inhibitor of LPL. Free ApoCIII is scavenged in the blood stream by other VLDL particles or the high density lipoprotein (HDL) particle as a part of the normal lipoprotein cycle. The elevation of ApoCIII concentration in plasma has been consistently correlated with the full spectrum of lipid metabolism disorders. There are rare disorders that result in overexpression of ApoCIII, which results in severe hyperlipidemia and illness of sufferers. There is also a rare null ApoCIII condition, found in Amish populations, that offers lipid protection. Even though these correlations have been observed, it has been viewed as responsive to the development of the indication, not causative.
Resent research has indicated that the presence of ectopic fat plays a major role in the organ dysfunction associated with these diseases. The development of lipid droplet and diacylglycerol (DAG) deposits in these tissues has been shown to disrupt the natural intra-cellular phospho-signalling pathways. The disruption of these pathways eventually leads to cellular and organ failure, resulting in the development of disease. However, the source of this high (DAG) content ectopic fat remains unknown.
It is proposed herein that inhibition of LPL leads to the development of these ectopic lipid accumulations developing into the spectrum of lipid metabolism disorders. Provided herein are inhibitors (antagonists) of ApoCIII, which prevent its ability to inhibit LPL, thereby preserving the LPL activity. This preservation will maintain the efficient conversion of VLDL to LDL and the generation of these ectopic lipid metabolism byproducts.